The Laboratory for Psychopharmacological/Biomedical Research has been a key component of the CRC since its inception in 1986. Significant findings have include the demonstration that treatment of depression with standard tricyclic agents remains efficacious even in the oldest and most frail of patients, that those depressions associated with "failure to thrive" and dementia differ in treatment response from other disorders and that medications commonly used for treatment of medical disorders in late life can cause psychiatric symptoms. It provides an ongoing infrastructure to enable pharmacological and biomedical research through the conduct of its own intrinsic research, facilitating collaborative research with CRC scientists and others, and outreach/consultative activities with a wide array of investigators and trainees. It also actively participates in multi-center clinical trials of the treatment of the mental disorders of late life, and works to develop these studies. This application requests support for the Laboratory to continue to provide an enabling infrastructure for this line of investigation. It also requests support for three specific pilot investigations: 1) A double-blind, placebo- controlled, randomized clinical trial of venlafaxine for the treatment of depression and pain associated with osteoarthritis. This is an intervention development study designed to provide information on the value of pharmacological treatment for the most common disabling condition in late life and to advance our understanding of the treatment-relevant interactions between depression and pain. 2) A study of the prevalence of subcortical and deep white matter hyperintensities, and of their association with cognitive (e.g., executive function) deficits and anhedonia or apathy (non-depressed) patients with diabetes. This study is designed to determine whether patients at high risk for "subclinical cerebrovascular disease" exhibit psychiatric symptoms that may targets for (primary or secondary) preventative interventions. 3) Exploratory studies of the behavioral pharmacology of the inflammatory cytokines. These will include challenge studies in healthy young adult volunteers of the subjective, behavioral and physiological responses to typhoid vaccine, and treatment studies in frail elderly patients of Tumor Necrosis Facto antagonists. The research is designed to develop models for the treatment of cytokine-mediated sickness behavior and depression.